Direct N-H/ N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents

Article abstract of DOI:10.1021/acs.joc.8b01673

Unactivated aziridines are the core substructures in a plethora of bioactive natural products and serve as building blocks in organic synthesis. Despite this, very limited methods are available to access them directly from olefins, as most of the known me

Full text of DOI:10.1021/acs.joc.8b01673

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Note
Direct N-H/N-Me Aziridination of Unactivated Olefins
Using O-(Sulfonyl)hydroxylamines as Aminating Agents
Shekh Sabir, Chandra Bhan Pandey, Ajay K. Yadav, Bhoopendra Tiwari, and Jawahar Lal Jat
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01673 • Publication Date (Web): 07 Sep 2018
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The Journal of Organic Chemistry
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Direct N-H/N-Me Aziridination of Unactivated Olefins Using O-
(Sulfonyl)hydroxylamines as Aminating Agents
Shekh Sabir†, Chandra Bhan Pandey‡, Ajay K. Yadav†, Bhoopendra Tiwari*‡, and Jawahar L. Jat*†
†Department of Chemistry, Baba Saheb Bhim Rao Ambedkar University, Lucknow, India.
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‡Division of Molecular Synthesis & Drug Discovery, Centre of Biomedical Research, SGPGIMSꢀCampus, Raebareli Road,
Lucknow, India.
Supporting Information Placeholders
ABSTRACT: Unactivated aziridines are the core substructures in a plethora of bioactive natural products, and serve as building
blocks in organic synthesis. Despite this, very limited methods are available to access them directly from olefins, as most of the
known methods are devoted to their activated counterparts. Herein, we have developed a highly efficient Rh(II)ꢀcatalyzed method
for the direct preparation of unactivated aziridines from olefins using Oꢀ(sulfonyl)hydroxylamines as the aminating agent. The reacꢀ
tions proceed with a high stereospecificity.
The unactivated aziridines (NꢀH/NꢀMe) are in high demand
because of their presence in many natural, semiꢀsynthetic and
synthetic bioactive molecules.1 They also serve as important
building blocks in organic synthesis because of their remarkaꢀ
ble reactivity via ringꢀopening as well as ringꢀexpansion, and
rearrangements.2 The regioꢀ and stereoꢀspecific ring opening
of unprotected (unactivated) aziridines with different nucleoꢀ
philes (N, O, S, C) offers various functionalized unprotected
scaffolds like aminoꢀalcohols, diamines, thioꢀamines, haloꢀ
amines, etc.3 Whereas the methods for activated aziridines (e.
g., NꢀTs, NꢀNs, Nꢀacyl) preparation from alkenes are well esꢀ
tablished, the direct method for accessing nonꢀactivated aziriꢀ
dines are less explored, and most of these methods are multiꢀ
steps (Scheme 1).4,5 In 2014, Falck, Kurti, Ess and Coꢀworkers
(including the corresponding author of this manuscript) reꢀ
ported the first direct method for the preparation of NꢀH and
NꢀMe aziridines from alkenes using 2,4ꢀdinitrophenyl hydroxꢀ
ylamine (DPH) as the aminating agent in the presence of a
rhodium catalyst (Du Bois catalyst) (A, Figure 1).6 This eleꢀ
gant method requires DPH in stoichiometric amount that has
several intrinsic drawbacks. For instance, the byꢀproduct, 2,4ꢀ
dinitrophenol (DNP), interferes via undesired ring opening
reaction, both DPH and DNP are relatively unstable/explosive
in nature due to a high NO2/C ratio, DNP occasionally coꢀ
elutes along with the product during columnꢀchromatography,
etc. Improving their previous method, Kurti et al. demonstratꢀ
ed another protocol using hydroxylamineꢀOꢀsulfonic acid
(HOSA), instead of DPH, as the aminating reagent in the presꢀ
ence of 1.2 equivalent of pyridine
Scheme 1. General Methods to Access Unprotected Aziri-
dines
Vanol = 3,3′ꢀDiphenylꢀ2,2′ꢀbiꢀ1ꢀnaphthalol. Vapol = 2,2′ꢀDiphenylꢀ(4ꢀ
biphenanthrol. DppONH2 = Oꢀ(Diphenylphosphinyl)hydroxylamine.
and the same rhodium catalyst (B, Figure 1).7 This modificaꢀ
tion could overcome the drawbacks of their previous method
to a great extent, but: (i) necessitated the use of 1.2 equivalent
of pyridine, (ii) column chromatography was still necessary,
and (iii) the use of a relatively costly hexafluoroisopropanol
(HFIP) as the solvent.
We were interested to develop an atomꢀeconomical, addiꢀ
tive/baseꢀfree and possibly a column chromatographyꢀfree
method, as the strained aziridine rings frequently open during
silicaꢀgel purification. To achieve these objectives, the aminatꢀ
ing reagent desirably should: (i) exists in a non zwitterꢀionic
form, (ii) be stable and readily available, and (iii) essentially
generate a nonꢀinterfering byꢀproduct that can be easily
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saturated NaHCO3 aqueous solution; silica gel chromatography was not
needed. TFE 2,2,2ꢀtrifluroethanol. esp α,α,α,αꢀtetramethylꢀ1,3ꢀ
benzenedipropionic acid.
Scheme 2. Preparation of N-Me Aziridinesa
=
=
̍
̍
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Figure 1. Aminating Agents Used for N-H and N-Me
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Aziridination of alkenes
removed just by an aqueous workꢀup. In this regard, Oꢀ
sulfonylhydroxylamines (3, Figure 1) attracted our attention.
This class of reagents have been mainly explored for αꢀ
oxytosylation of carbonyl compounds, and C(Sp2)ꢀH as well as
C(Sp3)ꢀH amination.8 We herein report a rhodiumꢀcatalyzed
synthesis of NꢀMe and NꢀH aziridines from alkenes using Nꢀ
MethylꢀOꢀtosylhydroxylamine8
(3a)
and
2,4,6ꢀ
Me3C6H2S(O)2ONH2 (3b) as the aminating reagents,9 respecꢀ
tively.
Our study for NꢀMe aziridination began using methyl oleate
1a as the model substrate in the presence of 3a as the aminatꢀ
ing reagent in 2,2,2ꢀtrifluoroethanol (TFE) (Table 1). Under
this condition, both Fe(II)ꢀ and Fe(III)ꢀbased catalysts did not
produce the desired product (entries 1 and 2). Whereas CuBr
was found ineffective, Cu(OAc)2 and Cu(acac)2 could catalyze
the reaction to produce 2a in 20ꢀ35% yield (entries 3ꢀ5). The
yield improved significantly to 52% with FeSO4.7H2O (entry
6). Switching to various Rhꢀbased catalysts further improved
the yield of the reaction, eventually giving the desired product
in excellent yield (96%) with Rh2(esp)2 in 30 min (entry 9).
The lowering of the catalyst loading from 5 mol % to 1 mol %
did
aReaction condition unless otherwise mentioned: 1 (0.5 mmol), 3a (1.2
equiv.), Rh2(esp)2 (1 mol %), TFE (2.0 mL), rt. Yields are the isolated
b
o
c
yield after an aqueous workꢀup. Reaction was performed at ꢀ10 C. The
purity of this compound was checked by HPLC. dColumn purification was
required. 5 mol % of Rhꢀcatalyst was used. A mixture of TFE:CHCl3
(1:1) was used as the solvent.
e
f
Table 1. Reaction Condition Optimizationa
not affect the yield significantly (93%, entry 10). The screenꢀ
ing of various other solvents under a condition similar to entry
10 had detrimental effect on the reaction outcome (entries 11ꢀ
15). To our delight, a simple workꢀup using saturated NaHCO3
aqueous solution completely removed the byꢀproduct (TsOH),
giving the desired product with a good purity (by NMR).
Entry
1
Catalyst
FeCl2 (5 mol %)
Solvent
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
Yield (%)b
ꢀ
ꢀ
To explore the scope of this method, a variety of alkenes
were evaluated under the standard condition (as in entry 10,
Table 1). Both cisꢀ and transꢀalkenes reacted well within an
hour to give the corresponding aziridines in excellent yields
(2a and 2b, Scheme 2). Olefins bearing even unprotected hyꢀ
droxy group smoothly aziridinated with 91% (2c) isolated
yield, while its TBSꢀprotected derivative produced 2d in 95%
yield at a lower reaction temperature. This TBSꢀprotected
alkene/aziridine partially got deprotected on stirring the reacꢀ
tion at room temperature. Cyclic alkene also participated in the
reaction affording 2e with 96% yield. Switching to a terminal
alkene required a minor variation in the reaction condition as it
was sluggish under the above optimized condition and a proꢀ
longation of the reaction time under this condition led to the
decomposition of the product. This reaction proceeded well
with a slightly higher Rhꢀcatalyst loading of 5 mol% and at a
2
FeCl3 (5 mol %)
3
CuBr (5 mol %)
trace
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65
ꢀ
4
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16
Cu(OAc)2 (5 mol %)
Cu(acac)2 (5 mol %)
FeSO4.7H2O (5 mol %)
Rh2(OAc)2 (5 mol %)
Rh2(TFA)2 (5 mol %)
Rh2(esp)2 (5 mol %)
Rh2(esp)2 (1 mol %)
Rh2(esp)2(1 mol %)
Rh2(esp)2(1 mol %)
Rh2(esp)2 (1 mol %)
Rh2(esp)2 (1 mol %)
Rh2(esp)2 (1 mol %)
ꢀ
TFE
TFE
96c
93c
trace
ꢀ
EtOH
THF
CH3CN
DMF
CH2Cl2
TFE
trace
ꢀ
ꢀ
ꢀ
aReaction condition unless otherwise mentioned: 1a (0.25 mmol), 3a (1.2
equiv.), catalyst (1.0ꢀ5.0 mol %), solvent, rt, 16 h. bIsolated yield after
silica gel column chromatography. cIsolated yield after workꢀup using
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o
lower reaction temperature (ꢀ10 C), giving 2f in 63% isolated
yield.
dienoate (a conjugated diene ester) afforded 4b (85% yield)
and 4c (38% yield), respectively, as a single regiomer. Simple
as well as substituted styrenes were good substrates for this
reaction at lower temperature to give the corresponding NꢀH
aziridines in good yield (4d and 4f). βꢀNaphthyl styrene was
also examined to obtain 4e in 64% yield. Chalcone reacted
slowly to give the corresponding aziridine in 35% yield (4g).
We also examined our reaction on complex substrate like choꢀ
lesterol. Under the optimized condition with TFE as the solꢀ
vent, only a minor conversion was observed; the yield imꢀ
proved dramatically when a mixture of TFE:CHCl3 (1:1) was
used as the solvent (4h, 70% yield), albeit the reaction took a
longer time to complete (36 h). We expect these reactions to
follow the same mechanistic pathway as previously proposed
by Falck, Kurti and Ess.6
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8
We next investigated the regioselectivity of the reaction usꢀ
ing geraniol, which exclusively aziridinated at ꢁ6,7ꢀolefinic
position to furnish 2g in 73% yield. Different derivatives of
geraniol also
Scheme 3. Preparation of N-H Aziridinesa
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In conclusion, we have developed a direct, stereospecific
Rh(II)ꢀcatalyzed NꢀH/NꢀMe aziridination method for alkenes
using Oꢀ(sulfonyl)hydroxylamines as the aminating agents.
These reagents do not generate explosive/interfering byꢀ
products and do not require base (pyridine) as an additive.
This method provides various unactivated aziridines in good to
excellent yield and NꢀMe aziridines in many cases could be
isolated with high purity just after an aqueous workꢀup. Even
highly reactive and labile functional groups like keto, ester,
alcohol and silyl were well tolerated. The reactions proceeded
with a good chemoselectivity as neither the undesired aminaꢀ
tion nor the nitrene insertion on the aromatic ring was obꢀ
served.
aReaction condition unless otherwise stated: 1 (0.5 mmol), 3b (1.2 equiv.)
Rh2(esp)2 (1 mol %), TFE (2.0 mL), rt. Yields are isolated yield after silica
c
gel column chromatography. bReaction stirred at ꢀ10 °C. Reaction was
clean but with low conversion, and the olefin could be recovered. dA mixꢀ
ture of TFE:CHCl3 (1:1) was used as the solvent. e2.5 equiv. of 3b and 2.5
mol % of Rhꢀcatalyst was used.
EXPERIMENTAL SECTION
General Information: Unless otherwise specified, all reacꢀ
tions were carried out under an open atmosphere in a round
bottom flask. All aldehydes were of commercial quality and
used without further purification. The olefins 1b, 1i, 1l, 1m
and βꢀnaphthyl styrene were prepared following a literature
known procedure.10 Solvents were dried and distilled followꢀ
ing the standard procedures. TLC was carried out on preꢀ
coated plates (Merck silica gel 60, f254), and the spots were
visualized with UV light or by charring the plates dipped in
PMA or KMNO4 solution. The compounds were purified by
flash column chromatography using silica gel (230ꢀ400 mesh)
with distilled solvents. 1H and 13C NMR spectra were recorded
at 400 MHz instrument, and 100 MHz instrument, respectiveꢀ
ly, in CDCl3 as the solvent. Chemical shifts (δ) are given in
ppm. The residual solvent signals were used as references
(CDCl3: δ H = 7.26 ppm, δ C = 77.0 ppm). Highꢀresolution
mass spectrometry (HRMS) was performed on agilent 6530 Qꢀ
TOF using electrospray ionization (ESI) and a timeꢀofꢀflight
(TOF) analyzer, in positiveꢀion or negativeꢀion detection
mode.
reacted smoothly to give 2h and 2i in 94% and 96% yields,
respectively, as a single regiomer. This regioselectivity can be
attributed to the inductive deactivation of the proximal double
bond (ꢁ2,3) by acetoxy or benzoyloxy group towards aziridinaꢀ
tion. This observation was further supported by a much slower
reactivity of the electron deficient chalcone requiring 16 h for
completion of the reaction (2k). A mixture of TFE and CHCl3
(1:1) was used as the solvent as the chalcone was not soluble
in TFE alone. For conjugated diene ester also, the aziridination
occurred at the distal (ꢁ3,4) double bond selectively (2j, 58%
yield). Both electronꢀrich as well as electronꢀdeficient trisubꢀ
stituted styrenes smoothly reacted to give the desired products
(2l and 2m) in good yield, albeit the reaction was slower in the
case of electronꢀdeficient styrene. Tetraꢀsubstituted olefin, like
βꢀionone, failed to react under this optimized condition for Nꢀ
Me (as well as for NꢀH) aziridination. It is worth noting that
all the reactions proceeded with high stereospecificity and
without formation of any allylic aminated side product.
After demonstrating the method for NꢀMe aziridination, we
turned our attention to the direct NꢀH aziridination of alkenes.
The literature survey and our own studies using unprotected
analog of 3a (TsONH2) to achieve NꢀH aziridination was not
successful as this reagent was unstable under this condition. A
2,4,6ꢀtrimethyl derivative of tosyl hydroxylamine (3b, Scheme
3) was found to be a good aminating agent under a condition
similar to Scheme 2. Under this condition, different alkenes
reacted well to give the desired products in good to excellent
yield. For example, methyl oleate furnished the NꢀH aziridine
4a in 83% yield. Geranyl acetate & (2E,4Z)ꢀethyl decaꢀ2,4ꢀ
General Procedure for NꢀH and NꢀMe Aziridination: To a
round bottom flask equipped with a magnetic stirring bar, was
added alkene 1 (0.5 mmol), aminating agent 3a or 3b (1.2
equiv.) and TFE (2 mL) at room temperature. To this stirred
solution, Rh2(esp)2 (1 mol %) was added. The reaction mixture
was stirred at the specified temperature and monitored by
TLC. After completion, the reaction mixture was diluted with
CH2Cl2 (10 mL) and washed with a saturated aqueous Naꢀ
HCO3 solution (2 x 5 mL). The aqueous layer was extracted
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twice with CH2Cl2 (5 mL) and the combined organic layer was
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(m, 0.5H), 1.42.1.33 (m, 1H), 1.29ꢀ1.11 (m, 2H), 1.07ꢀ1.01
(m, 2H), 0.95 (t, J = 7.4Hz, 1H), 0.91ꢀ0.85 (m, 8H), 0.07ꢀ0.03
(m, 6H). 13C NMR (100 MHz, CDCl3) δ 62.2, 61.3, 48.3, 44.4,
44.0, 39.8, 39.1, 38.5, 36.4, 29.6, 29.1, 26.1, 25.9, 19.0, 18.3,
12.7, 11.4, 1.0, ꢀ5.3. HRMS (ESI) m/z [M+H ]+ calcd for
C13H30 NOSi, 244.2091; found, 244.2090.
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7
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dried over anhydrous Na2SO4.
Purification method for Scheme 2: Organic layer was concenꢀ
trated in vacuo to afford the pure desired product 2, unless
reported otherwise.
Purification method for Scheme 3: The crude product obtained
after concentration of the organic layer in vacuo was purified
by silica gel column chromatography to give the pure desired
product 4 using 1% Bu3N in EtOAc/hexane or MeOH/CH2Cl2
as an eluent.
7ꢀMethylꢀ7ꢀazabicyclo[4.1.0]heptanes (2e):11 Following the
general aziridination procedure, the title aziridine was obꢀ
tained as a light yellow oil (53 mg, 96% yield). TLC: Rf = 0.4
(50% EtOAc in hexane), whose spectral data were in accord
with the literature values.
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(E)ꢀ3,7ꢀDimethyloctaꢀ2,6ꢀdienyl 4ꢀnitrobenzoate (1j): To a
solution of geraniol (200 mg, 1.29 mmol) and pꢀnitrobenzoyl
chloride (289 mg, 1.54 mmol) in CH2Cl2 (15 mL) at 0 oC, was
added pyridine ( 136 ꢂL, 1.54 mmol) and DMAP (18 mg, 0.15
mmol) and the reaction was stirred at room temperature for 18
h. After completion of the reaction, CH2Cl2 (10 mL) was addꢀ
ed and the organic layer was washed with water (2 x 5 ml) and
brine solution (5 ml). The organic layer was dried over anhyꢀ
drous Na2SO4, concentrated in vacuo and the crude product
was purified by silica gel column chromatography (2% EtOAc
in hexane) to give the title compound as a thick oil. (325 mg,
9ꢀ(1ꢀMethylaziridinꢀ2ꢀyl)nonanꢀ1ꢀol (2f): The product was
prepared following the general aziridination procedure and the
crude product was purified by silica gel column chromatogꢀ
raphy using Bu3N:MeOH:CH2Cl2 (1:2:97) as an eluent to give
the title compound as an oil (63 mg, 63% yield). TLC: Rf =
1
0.25 (5% MeOH in CH2Cl2). H NMR (400 MHz, CDCl3) δ
3.63 (t, J = 6.6 Hz, 2H), 2.30 (s, 3H), 1.70 (brs, 1H), 1.58ꢀ1.53
(m, 2H), 1.48 (d, J = 3.5 Hz, 1H), 1.40ꢀ1.17 (m, 17H), 1.11 (d,
J = 3.1, 1H). 13C NMR (100 MHz, CDCl3) δ 62.8, 53.4, 47.8,
40.8, 34.8, 32.9, 32.7, 29.6, 29.4, 29.3, 29.3, 27.5, 25.7.
HRMS (ESI) m/z [M+H]+ calcd. for C12H26NO: 200.2009,
found: 200.2017.
1
83%). TLC: Rf = 0.5 (5% EtOAc in hexane). H NMR (400
MHz, CDCl3) δ 8.28ꢀ8.23 (m, 2H), 8.22ꢀ8.17 (m, 2H), 5.49ꢀ
5.42 (m, 1H), 5.10ꢀ5.04 (m, 1H), 4.87 (d, J = 7.1 Hz, 2H),
2.14ꢀ2.03 (m, 4H), 1.76 (s, 3H), 1.65 (s, , 3H), 1.58 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 164.6, 150.4, 143.3, 135.8,
131.8, 130.6, 123.5, 123.4, 117.6, 62.7, 39.4, 26.2, 25.6, 17.6,
16.5. HRMS (ESI) [M+H]+ calcd. for C17H22NO4: 304.1543,
found: 304.1525.
Methyl 8ꢀ(1ꢀmethylꢀ3ꢀoctylaziridinꢀ2ꢀyl)octanoate (2a):6 Folꢀ
lowing the general aziridination procedure, the title aziridine
was obtained as a colorless oil (151 mg, 93% yield) whose
spectral data were in accord with the literature values.
(E)ꢀ3ꢀMethylꢀ5ꢀ(1,3,3ꢀtrimethylaziridinꢀ2ꢀyl)pentꢀ2ꢀenꢀ1ꢀol
(2g): The product was prepared following the general aziridiꢀ
nation procedure and the crude product was purified by silica
gel column chromatography using Bu3N:MeOH:CH2Cl2
(1:4:95) as an eluent to give the title product as an oil (66 mg,
73% yield). TLC: Rf = 0.3 (10% MeOH in CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ 5.47ꢀ5.40 (m, 1H), 4.15 (d, J = 6.9
Hz, 2H), 2.36 (s, 3H), 2.20ꢀ2.04 (m, 2H), 1.68 (s, 3H),
1.58ꢀ1.42 (m, 2H), 1.24 (s, 1H), 1.17 (s, 3H), 1.09 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 139.2, 123.7, 59.3, 52.0, 39.5,
39.3, 37.7, 27.5, 21.6, 17.9, 16.2. HRMS (ESI) m/z [M+H]+
calcd. for C11H22NO: 184.1623, found: 184.1642.
2,3ꢀDibutylꢀ1ꢀmethylaziridine(2b): Following the general
aziridination procedure, the title product was obtained as a
colorless oil (80 mg, 94% yield). TLC: Rf = 0.3 (50% EtOAc
(E)ꢀ3ꢀMethylꢀ5ꢀ(1,3,3ꢀtrimethylaziridinꢀ2ꢀyl)pentꢀ2ꢀenꢀ1ꢀyl
acetate (2h):6 Following the general aziridination procedure,
the title aziridine was obtained as an oil (106 mg, 94% yield).
1H NMR and 13C NMR data were in accord with the literature
value.
1
in hexane). H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H), 1.64ꢀ
1.56 (m, 2H), 1.46ꢀ1.28 (m, 11H), 0.93ꢀ0.86 (m, 6H). 13C
NMR (100 MHz, CDCl3) δ 47.2, 42.9, 38.6, 32.8, 30.6, 29.6,
25.3, 22.6, 22.5, 14.0, 13.9. HRMS (ESI) m/z [M+H]+ calcd.
for C11H24N:170.1903, found: 170.1903.
(E)ꢀ3ꢀMethylꢀ5ꢀ(1,3,3ꢀtrimethylaziridinꢀ2ꢀyl)pentꢀ2ꢀenyl 4ꢀ
nitrobenzoate (2i): Following the general aziridination proceꢀ
dure, the title product was obtained as a thick yellow liquid.
(158 mg, 96% yield). TLC: Rf = 0.3 (40% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ 8.28ꢀ8.23 (m, 2H), 8.21ꢀ8.16
(m, 2H), 5.52ꢀ5.44 (m, 1H), 4.87 (d, J = 7.1 Hz, 2H), 2.34 (s,
3H), 2.25ꢀ2.09 (m, 2H), 1.77 (s, 3H), 1.62ꢀ1.43 (m, 2H), 1.15
(s, 3H), 1.07 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 164.6,
150.4, 143.1, 135.8, 130.6, 123.4, 117.9, 62.6, 51.8, 39.5,
39.3, 37.7, 27.5, 21.7, 17.9, 16.4. HRMS (ESI) m/z [M+H]+
calcd. for C18H25N2O4: 333.1809, found: 333.1815.
2ꢀ(3ꢀEthylꢀ1ꢀmethylaziridinꢀ2ꢀyl)ethanol (2c): Following the
general aziridination procedure, the title product was obtained
as a paleꢀyellow oil (58 mg, 91% yield). TLC: Rf = 0.3 (5%
1
MeOH in CH2Cl2). H NMR (400 MHz, CDCl3) δ 3.84ꢀ3.71
(m, 2H), 2.34 (s, 3H), 1.76ꢀ1.68 (m, 1H), 1.56ꢀ1.29 (m, 4H),
1.25ꢀ1.19 (m, 1H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 61.9, 47.8, 46.2, 43.1, 29.5, 21.2, 11.8. HRMS
(ESI) m/z [M+H]+ calcd. for C7H16NO: 130.1226, found:
130.1225.
2ꢀ(2ꢀ(tertꢀButyldimethylsilyloxy)ethyl)ꢀ3ꢀethylꢀ1ꢀmethyl
aziridine (2d): The product was prepared following the genꢀ
eral aziridination procedure and the crude product was purified
(E)ꢀEthylꢀ3ꢀ(1ꢀmethylꢀ3ꢀpentylaziridinꢀ2ꢀyl)acrylate (2j): The
product was prepared following the general aziridination proꢀ
cedure and the crude product was purified by silica gel column
chromatography using Bu3N:EtOAc:hexane (1:29:70) as an
eluent to give the title product as a colorless oil (64 mg, 58%
by
silica
gel
column
chromatography
using
Bu3N:EtOAc:hexane (1:29:70) as an eluent to give the title
product as a colorless oil (115 mg, 95% yield). TLC: Rf = 0.2
1
1
yield). TLC: Rf = 0.6 (20% EtOAc in hexane). H NMR (400
(50% EtOAc in hexane). H NMR (400 MHz, CDCl3; a mixꢀ
MHz, CDCl3) δ 6.71 (dd, J = 15.6, 7.8 Hz, 1H), 6.00 (dd, J =
15.6, 0.7 Hz, 1H), 4.22ꢀ4.09 (m, 2H), 2.38 (s, 3H), 1.91 (t, J =
ture of invertomers) δ 3.77ꢀ3.65 (m, 2H), 2.39 (s, 1.5H), 2.38
(s, 1.5H), 1.90ꢀ1.78 (m, 0.5H), 1.71ꢀ1.53 (m, 3H), 1.52ꢀ1.43
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7.1 Hz, 1H), 1.59 (q, J = 5.8 Hz, 1H), 1.31ꢀ1.19 (m, 10H),
MHz, CDCl3) δ 6.71 (dd, J = 15.6, 8.3 Hz, 1H), 6.07 (d, J =
15.6 Hz, 1H), 4.23ꢀ4.14 (m, 2H), 2.89 (brs, 1H), 2.70 (brs,
1H), 2.33 (d, J = 5.3 Hz, 1H), 1.54ꢀ1.36 (m, 2H), 1.34 ꢀ1.19
(m, 7H), 0.87 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 165.9, 145.6, 123.7, 60.3, 38.9, 35.4, 31.4, 29.1, 27.3, 22.5,
14.2, 13.9. HRMS (ESI) [M+H]+ calcd. for C12H22NO2:
212.1645, found: 212.1633.
2ꢀMethylꢀ2ꢀphenylaziridine (4d):6 The product was prepared
following the general aziridination procedure and the crude
product was purified by silica gel column chromatography
using Bu3N:EtOAc:hexane (1:19:80) as an eluent to give the
title compound as a colorless oil (37 mg, 55% yield). TLC: Rf
= 0.3 (50% EtOAc in hexane), whose spectral data were in
accord with the literature values.
0.88 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 166.0,
145.9, 123.0, 60.1, 49.3, 47.4, 45.0, 31.4, 28.4, 27.2, 22.5,
14.2, 13.9. HRMS (ESI) m/z [M+H]+ calcd. for C13H24NO2:
226.1802, found: 226.1800.
1
2
3
4
5
6
7
8
(3ꢀ(4ꢀChlorophenyl)ꢀ1ꢀmethylaziridinꢀ2ꢀyl) (phenyl) methꢀ
anone (2k): The product was prepared following the general
aziridination procedure and the crude product was purified by
silica gel column chromatography using Bu3N:EtOAc:hexane
(1:5:94) as an eluent to give the title compound as a light yelꢀ
low sticky semiꢀsolid (81 mg, 60% yield). TLC: Rf = 0.5 (10%
EtOAc in hexane). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J =
7.4 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.49 (t, J = 7.7, 2H), 7.32
ꢀ 7.23 (m, 4H), 3.53 (d, J = 2.4 Hz, 1H), 3.33 (d, J = 2.2 Hz,
1H), 2.67 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.1, 137.9,
137.2, 133.5, 133.2, 128.7, 128.5, 128.4, 127.5, 48.7, 48.5,
38.6. HRMS (ESI) m/z [M+H]+ calcd. for C16H15ClNO:
272.0837, found: 272.0843.
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(E)ꢀ2ꢀMethylꢀ3ꢀ(naphthaleneꢀ2ꢀyl)aziridine (4e): The product
was prepared following the general aziridination procedure
and the crude product was purified by silica gel column chroꢀ
matography using Bu3N:EtOAc:hexane (1:19:80) as an eluent
to give the title compound as a colorless oil (59 mg, 64%
3ꢀ(4ꢀMethoxyphenyl)ꢀ1,2,2ꢀtrimethylaziridine (2l): The prodꢀ
uct was prepared following the general aziridination procedure
and the crude product was purified by silica gel column chroꢀ
matography using Bu3N:EtOAc:hexane (1:5:94) as an eluent
to give the title compound as a light yellow sticky semiꢀsolid
(74 mg, 78% yield). TLC: Rf = 0.5 (10% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ 7.22ꢀ7.17 (m, 2H), 6.87ꢀ6.81
(m, 2H), 3.79 (s, 3H), 2.54 (s, 3H), 2.28 (s, 1H), 1.33 (s, 3H),
0.88 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 158.3, 130.8,
128.4, 113.4, 55.2, 53.9, 42.3, 39.5, 21.4, 17.6. HRMS (ESI)
m/z [M+H]+ calcd. for C12H17NO: 192.1344, found: 192.1389.
1
yield) TLC: Rf = 0.4 (20% EtOAc in hexane). H NMR (400
MHz, CDCl3) δ 7.83ꢀ7.75 (m, 3H), 7.68 (s, 1H), 7.49ꢀ7.39 (m,
2H), 7.31ꢀ7.24 (m, 1H), 2.83 (d, J = 2.9 Hz, 1H), 2.27ꢀ2.19
(m, 1H), 1.42 (d, J = 5.4Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 137.8, 133.3, 132.6, 128.1, 127.6, 127.5, 126.1, 125.5, 124.3,
123.5, 40.6, 37.2, 19.6. HRMS (ESI) m/z [M+H]+ calcd. for
C13H14N, 184.1048; found, 184.1118.
2,2ꢀDimethylꢀ3ꢀphenylaziridine (4f):6 The product was preꢀ
pared following the general aziridination procedure and the
crude product was purified by silica gel column chromatogꢀ
raphy using Bu3N:EtOAc:hexane (1:19:80) as an eluent to
give the title compound as a colorless oil (53 mg, 72% yield).
TLC: Rf = 0.5 (50% EtOAc in hexane), whose spectral data
were in accord with the literature values.
(3ꢀ(4ꢀChlorophenyl)aziridinꢀ2ꢀyl)(phenyl)methanone (4g):12
The product was prepared following the general aziridination
procedure and the crude product was purified by silica gel
column chromatography using Bu3N:EtOAc:hexane (1:9:90)
as an eluent to give the title compound as a light yellow sticky
solid (45 mg, 35% yield), whose spectral data were in accord
with the literature values.
1,2,2ꢀTrimethylꢀ3ꢀ(4ꢀnitrophenyl)aziridine (2m): The product
was prepared following the general aziridination procedure
and the crude product was purified by silica gel column chroꢀ
matography using Bu3N:EtOAc:hexane (1:5:94) as an eluent
to give the title compound as a light yellow sticky semiꢀsolid
(62 mg, 60% yield). TLC: Rf = 0.5 (10% EtOAc in hexane).
1H NMR (400 MHz, CDCl3) δ 8.18ꢀ8.12 (m, 2H), 7.47ꢀ7.42
(d, 2H), 2.57 (s, 3H), 2.39(s, 1H), 1.38 (s, 3H), 0.87 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 146.9, 146.7, 128.18, 123.2,
53.6, 44.2, 39.3, 21.3, 17.6. HRMS (ESI) m/z [M+H]+ calcd.
for C11H14N2O2: 207.1139, found: 207.1089.
Methyl 8ꢀ(3ꢀoctylaziridinꢀ2ꢀyl)octanoate 4a:6 The product was
prepared following the general aziridination procedure and the
crude product was purified by silica gel column chromatogꢀ
raphy using Bu3N:MeOH:CH2Cl2 (1:2:97) as an eluent to give
the title compound as an oil (129 mg, 83% yield), whose specꢀ
tral data were in accord with the literature values.
Aziridinylcholestanꢀ3ꢀβꢀol (4h):6 The product was prepared
following the general aziridination procedure and the crude
product was purified by silica gel column chromatography
using EtOAc:hexane (60:40) as an eluent to give the title comꢀ
1
pound as an off white solid (73 mg, 70% yield). H and 13C
NMR data were in accord with the literature values.
(E)ꢀ5ꢀ(3,3ꢀDimethylaziridinꢀ2ꢀyl)ꢀ3ꢀmethylpentꢀ2ꢀenyl aceꢀ
tate (4b):6 The product was prepared following the general
aziridination procedure and the crude product was purified by
silica gel column chromatography using Bu3N:MeOH:CH2Cl2
(1:2:97) as an eluent to give the title compound as oil (89 mg,
85% yield), whose spectral data were in accord with the literaꢀ
ture values.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(E)ꢀEthyl 3ꢀ(3ꢀpentylaziridinꢀ2ꢀyl)acrylate (4c): The product
was prepared following the general aziridination procedure
and the crude product was purified by silica gel column chroꢀ
matography using Bu3N:EtOAc:hexane (1:49:50) as an eluent
to give the title compound as a light yellow oil (40 mg, 38%
1H, 13C and HPLC spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
1
yield). TLC: Rf = 0.4 (40% EtOAc in hexane). H NMR (400
Eꢀmail: jatjawahar@gmail.com, btiwari@cbmr.res.in
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Page 6 of 7
Aziridinations and Asymmetric Nitrene Insertions into CH
Bonds. Chem. Rev. 2003, 103, 2905ꢀ2919.
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
J. L. J. thanks DSTꢀSERB (YSS/2015/000838) and UGCꢀBSR
(No.F.30ꢀ382/2017), New Delhi for the grants. B. T. gratefully
acknowledge the SERB, New Delhi, for the funding
(EMR/2015/00097).
5. Nonꢀactivated aziridination: For reviews, see: (a) Sabir, S.; Kuꢀ
mar, G.; Jat, J. L., Unprotected Aziridines: A Synthetic Overview.
Asian J. Org. Chem. 2017, 6, 782ꢀ793; and also reference 4. For
reports, see: (b) Meszaros, A.; Szekely, A.; Stirling, A.; Novak,
Z., Design of Trifluoroalkenyl Iodonium Salts for a Hypervalenꢀ
cy Aided Alkenylation–Cyclization Strategy: Metal Free Conꢀ
struction of Aziridine Rings. Angew. Chem. Int. Ed. 2018, 57,
6643ꢀ6647. (c) Wang, H.; Yang, J. C.; Buchwald, S. L., CuHꢀ
Catalyzed Regioselective Intramolecular Hydroamination for the
Synthesis of AlkylꢀSubstituted Chiral Aziridines. J. Am. Chem.
Soc. 2017, 139, 8428ꢀ8431. (d) Varszegi, C.; Ernst, M.; Van Laar,
F.; Sels, B. F.; Schwab, E.; De, D. V. A Miceller Iodide Cataꢀ
lyzed Synthesis of Unprotected Aziridiens from Styrene and
Ammonia. Angew. Chem. Int. Ed. 2008, 47, 1477ꢀ1480. (e) Lu,
Z.; Zhang, Y.; Wulff, W. D., Direct Access to NꢀHꢀAziridines
from Asymmetric Catalytic Aziridination with Borate Catalysts
Derived from Vaulted Binaphthol and Vaulted Biphenanthrol
Ligands. J. Am. Chem. Soc. 2007, 129, 7185ꢀ7194. (f) Lebel, H.
Lectard, S.; Parmentier, M., CopperꢀCatalyzed Alkene Aziridinaꢀ
tion with NꢀTosyloxycarbamates. Org. Lett. 2007, 9, 4797ꢀ4800.
(g) Koohang, A.; Stanchina, C. L.; Coates, R. M., Regioꢀand Steꢀ
reoselective synthesis of NꢀH Aziridiens NꢀN Bond Reduction of
NꢀQuinazolinylaziridines. Tetrahedron 1999, 55, 9669ꢀ9686. (h)
Vedejs, E.; Sano, H., Synthesis of Nꢀmethoxy and NꢀH Aziridines
from Alkene. Tetrahedron Lett. 1992, 33, 3261ꢀ3264. (i) Bottaro,
J. C., Stereospecific Conversion of Olefins into Aziridines by pꢀ
Tolylꢀsulphonylhydroxylamine. J. Chem. Soc., Chem. Commun.
1980, 560.
6. Jat, J. L.; Paudyal, M. P.; Gao, H.; Xu, Q.ꢀL.; Yousufuddin, M.;
Devarajan, D.; Ess, D. H.; Kürti, L.; Falck, J. R. Direct Stereoꢀ
specific Synthesis of Unprotected NꢀH and NꢀMe Aziridines from
Olefin. Science 2014, 343, 61ꢀ65.
7. Ma, Z.; Zhou, Z.; Kurti, L. Direct and Stereospecific Synthesis of
NꢀH and NꢀAlkyl Aziridines from Unactivated Olefins Using
HydroxylamineꢀOꢀ Sulfonic Acid. Angew. Chem. Int. Ed. 2017,
56, 9886ꢀ9890.
8. For a review, see: (a) Sabir, S.; Kumar, G.; Jat, J. L. Oꢀ
Substituted Hydroxyl Amine Reagents: An Overview of Recent
Synthetic Advances. Org. Biomol. Chem., 2018, 16, 3314ꢀ3327.
For recent articles, see: (b) Munnuri, S.; Adebesin, A. M.;
Paudyal, M. P.; Yousufuddin, M.; Dalipe, A.; Falck, J. R. Cataꢀ
lystꢀControlled Diastereoselective Synthesis of Cyclic Amines via
C−H Functionalization. J. Am. Chem. Soc. 2017, 139, 18288ꢀ
18294. (c) Paudyal, M. P.; Adebesin, A. M.; Burt, S. R.; Ess, D.
H.; Ma, Z.; Kürti L.; Falck, J. R. Dirhodiumꢀcatalyzed CꢀH Arene
Amination Using Hydroxylamines. Science 2016, 353, 1144ꢀ
1147. (d) John, O. R. S.; Killeen, N. M.; Knowles, D. A.; Yau, S.
C.; Bagley, M. C.; Tomkinson, N. C. O. Direct αꢀOxytosylation
of Carbonyl Compounds:ꢃ OneꢀPot Synthesis of Heterocycles.
Org. Lett. 2007, 9, 4009ꢀ4012.
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Liu, H. W. Enzymatic Chemistry of Cyclopropane, Epoxide, and
Aziridine Biosynthesis. Chem. Rev. 2012, 112, 1681ꢀ1709. (b)
Botuha, C.; Chemla, F.; Ferreira, F.; PerezꢀLuna, A. Aziridines in
Natural Product Synthesis. Heterocycles in Natural Product Synꢀ
thesis (Eds.: Majumdar, K. C.; Chattopadhyay, S. K.), Wileyꢀ
VCH, Weinheim, Germany, 2011, pp. 3ꢀ39. (c) Ismail, F. M.;
Levitsky, D. O.; Dembitsky, V. M. Aziridine Alkaloids as Potenꢀ
tial Therapeutic Agents. Eur. J. Med. Chem. 2009, 44, 3373ꢀ3387.
(d) Watson, I. D. G.; Yu, L.; Yudin, A. K. Advances in Nitrogen
Transfer Reactions Involving Aziridines. Acc. Chem. Res. 2006,
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in Situ Activation for DNAꢀTargeting Antitumor Agents. Chem.
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ides’ ugly cousins? Chem. Soc. Rev. 2002, 31, 247ꢀ258. (g)
Dahanukar, V. H.; Zavialov, L. A. Aziridines and Aziridinium
ions in the Practical Synthesis of Pharmaceutical Intermediatesꢀa
Perspective. Curr. Opin. in Drug Dis. Dev. 2002, 5, 918ꢀ927.
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Branco, P. S.; Afonso, C. A. M. Ring Opening of 6ꢀ
Azabicyclo[3.1.0]hexꢀ3ꢀenꢀ2ꢀols in Water Under Mild Condiꢀ
tions. Eur. J. Org. Chem. 2016, 2048ꢀ2053. (b) CraigII, R. A.;
O’Connor, N. R.; Goldberg, A. F. G.; Stoltz, B. M. Stereoselecꢀ
tive Lewis Acid Mediated (3+2) Cycloadditions of NꢀHꢀ and Nꢀ
Sulfonylaziridines with Heterocumulenes. Chem. Eur. J. 2014,
20, 4806ꢀ4813. (c) Ghorai, M. K.; Nanaji, Y.; Yadav, A. K. Ring
Opening/CꢀN Cyclization of Activated Aziridines with Carbon
Nucleophiles: Highly Diastereoꢀ and Enantioselective Synthesis
of Tetrahydroquinolines. Org. Lett. 2011, 13, 4256ꢀ4259. (d) Floꢀ
rio, S.; Luisi, R. Aziridinyl Anions: Generation, Reactivity, and
Use in Modern Synthetic Chemistry. Chem. Rev. 2010, 110,
5128ꢀ5157. (e) Singh, G. S.; D'hooghe, M.; Kimpe, N. D. Syntheꢀ
sis and Reactivity of CꢀHeteroatomꢀSubstituted Aziridines. Chem.
Rev. 2007, 107, 2080ꢀ2135. (f) Lowden P. A. S. Ed: Yudin, A. K.
Aziridines and Epoxides in Organic Synthesis. WileyꢀVCH,
Weinheim, 2006. (g) Hu, X. E. Nucleophilic Ring Opening of
Aziridines. Tetrahedron 2004, 60, 2701ꢀ2743.
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3. For recent reviews and article, see: (a) Luginina, J.; Turks, M.
NonꢀActivated Aziridines as a Building Blocks for the Synthesis
of AzaꢀHeterocycles. Chem. Heterocycle. Comp. 2016, 52, 773ꢀ
775. (b) Stanković, S.; D'hooghe, M.; Catak, S.; Eum, H.; Waroꢀ
quier, M.; Speybroeck, V. V.; Kimpe, N. D.; Ha, H.ꢀJ. Regioseꢀ
lectivity in the Ring Opening of Nonꢀactivated Aziridines. Chem.
Soc. Rev. 2012, 41, 643ꢀ665. (c) Kelley, B. T.; Joullie, M. M.
Ring Opening of a Trisubstituted Aziridine With Amines: Regioꢀ
and Stereoselective Formation of Substituted 1,2ꢀ Diamines. Org.
Lett. 2010, 12, 4244ꢀ4247. (d) Forbeck, E. M.; Evans, C. D.; Gilꢀ
leran, J. A.; Li, P.; Joullie, M. M. A Regioꢀ and Stereoselective
Approach to Quaternary Centers from Chiral Trisubstituted
Aziridines. J. Am. Chem. Soc. 2007, 129, 14463ꢀ14469.
9. For selected recent articles, see: (a) Chavez, D. E.; Bottaro, J. C.;
Petrie, M.; Parrish, D. A. Synthesis and Thermal Behavior of a
Fused, Tricyclic 1,2,3,4ꢀTetrazine Ring System. Angew. Chem.
Int. Ed. 2015, 54, 12973ꢀ12975. (b) Mendiola, J.; Rinco´n, J. A.;
Mateos, C.; Soriano, J. F.; Frutos, O. D.; Niemeier, J. K.; Davis,
E.
M.
Preparation,
Use,
and
Safety
of
Oꢀ
Mesitylenesulfonylhydroxylamine. Org. Process Res. Dev. 2009,
13, 263ꢀ267. (c) Martı´nez, V.; Burgos, C.; A´lvarezꢀBuilla, J.;
Ferna´ndez, G.; Domingo, A.; Garcı´aꢀNieto, R.; Gago, F.; Manꢀ
zanares, I.; Cuevas, C.; Vaquero, J. J. Benzo[f]azino[2,1ꢀ
a]phthalazinium Cations:ꢃ Novel DNA Intercalating Chromoꢀ
phores with Antiproliferative Activity. J. Med. Chem. 2004, 47,
1136ꢀ1148. (d) Valenciano, J.; SánchezꢀPavón, E.; Cuadro, A.
M.; Vaquero, J. J.; AlvarezꢀBuilla, J. 1,4ꢀ and 1,3ꢀDipolar Reacꢀ
tivity of αꢀAlkoxycarbonylcycloimmonium NꢀAminides with Diꢀ
4. For selected reviews on aziridines preparation (activate as well as
unactivated), see: (a) Callebaut, G.; Meiresonne, T.; Kimpe, N.
D.; Mangelinckx, S. Synthesis and Reactivity of 2ꢀ
(Carboxymethyl)aziridine Derivatives. Chem. Rev. 2014, 114,
7954ꢀ8015. (b) Degennaro, L.; Trinchera, P.; Luisi, R. Recent
Advances in the Stereoselective Synthesis of Aziridines. Chem.
Rev. 2014, 114, 7881ꢀ7929. (c) Pellissier, H. Recent Developꢀ
ments in Asymmetric Aziridination. Adv. Synth. Catal. 2014, 356,
1899ꢀ1935. (d) Muller, P.; Fruit, C. Enantioselective Catalytic
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